A new autosomal recessive mouse mutation, Purkinje cell degeneration (ped), is described. Mutants exhibit a moderate ataxia beginning at 3 to 4 weeks of age. The ataxia results from postnatal degeneration of virtually all cerebellar Purkinje cells beginning around 15 to 18 days of age and progressing rapidly over the next 2 weeks. In addition to the cerebellar disease there is slow progressive degeneration in the retina (photoreceptor cells) and olfactory bulb. Also, adult males have abnormal sperm.Because of the uniform, stereotyped, and relatively simple organization of the cerebellar cortex many neuroscientists have chosen to study its functional organization (1), cytology and synaptic architecture (2), or development (3). Since the most obvious functions of the cerebellum involve posture and motor coordination, most mutations will affect behavior and are readily detected. In mice, a number of cerebellar mutants have been described (4) MATERIALS AND METHODSThe pcd mutation occurred in the C57BR/cdJ strain at The Jackson Laboratory. Because of the poor breeding performance of this strain, pcd/pcd females were mated to C3H/ HeJ males and the Fj-animals were intercrossed to produce pcd/pcd F2 females. These females were then crossed back to C57BR/cdJ males and the pcd mutation was maintained thereafter by brother-sister matings. The mutant gene is also being transferred to the C57BL/6J strain. The animals used in this study came from both lines.For histological studies, the mice were fixed by perfusion through the heart with 1% formaldehyde and 1.25% glutaraldehyde in 0.1 M sodium phosphate buffer, pH 7.2. The brains were removed, dehydrated, and embedded in either paraffin or celloidin. Sections were cut at 7 or 20 gm and stained with cresyl violet. In addition, pieces of cerebellum and eyes were postfixed in OS04, dehydrated, embedded in an Epon-Araldite mixture, and sectioned at 1 Am, and the sections were stained with toluidine blue.The various brain regions are designated according to the atlas of Sidman et al. (14). Day of birth is considered day 0.To determine if there was any difference in body weights between mutants and controls, all young in 8 litters were earmarked on day 15

The expression of Sry in the undifferentiated, bipotential genital ridges of mammalian XY fetuses initiates testis development and is hypothesized to do so by directing supporting cell precursors to develop as Sertoli cells and not as granulosa cells. To directly test this hypothesis, transgenic mice expressing EGFP under the control of the Sry promoter were produced. After establishing that the transgene was expressed in fetal gonads similarly to endogenous Sry, the spatial and temporal expression of the Sry-EGFP transgene was investigated in developing gonads by using confocal microscopy and immunofluorescent histochemistry. This analysis indicated: (1) Sry is first expressed in cells located centrally in the genital ridge and then later in cells located at the cranial and caudal poles, (2) Sry is expressed exclusively in pre-Sertoli cells in the urogenital ridge, and (3) Sertoli and granulosa cells develop from a common precursor. These results support the hypothesis that Sry initiates testis differentiation by directing the development of supporting cell precursors as Sertoli rather than granulosa cells. Furthermore, the Sry expression pattern explains the nonrandom distribution of testicular and ovarian tissue in mammalian ovotestes.

Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous disease involving abnormalities of melanosomes, platelet dense granules and lysosomes. Here we have used positional candidate and transgenic rescue approaches to identify the genes mutated in ruby-eye 2 and ruby-eye mice (ru2 and ru, respectively), two 'mimic' mouse models of HPS. We also show that these genes are orthologs of the genes mutated in individuals with HPS types 5 and 6, respectively, and that their protein products directly interact. Both genes are previously unknown and are found only in higher eukaryotes, and together represent a new class of genes that have evolved in higher organisms to govern the synthesis of highly specialized lysosome-related organelles.

A new dominant mutation in the laboratory mouse, hypophosphatemia (gene symbol Hyp), has been identified. The Hyp gene is located on the X-chromosome and maps at the distal end. Mutant mice are characterized by hypophosphatemia, bone changes resembling rickets, diminished bone ash, dwarfism, and high fractional excretion of phosphate anion (low net tubular reabsorption We report the discovery of an X-linked dominant mutation named hypophosphatemia (gene symbol Hyp) in the laboratory mouse. Our findings indicate that the disease seen in the hypophosphatemic mouse is similar to XLH. Because both diseases are inherited as X-linked dominants, it is highly probable that the human and mouse diseases are caused by mutations affecting the homologous gene. Accordingly, the mouse should be a valuable model for elucidation of the basic defect in human XLH. MATERIALS AND METHODSOrigin and Genetics. In 1966, six male mice with shortened trunk and hind limbs were noted in a linkage experiment at the Jackson Laboratory. By appropriate crosses, the new mutation was shown to be dominant and X-linked. Because the affected mice had a low serum phosphorus concentration, the mutation was named hypophosphatemia, gene symbol Hyp. Soon after its discovery, the mutant Hyp allele was transferred to the C57BL/6J inbred strain by repeated matings of Hyp/+ females to C57BL/6J +/Y males. All growth and physiological studies were conducted on mice of the C57BL/6J-Hyp strain.Diet. Unless otherwise noted, all mice were fed the mouse diet Old Guilford 96W containing 22.5% protein, 7.5% fat, 0.6% vitamin supplement, 0.22% calcium, and 0.74% phosphorus (wt/wt). The drinking water was acidified. Food and water were available ad libitum.Linkage. In order to determine the position of Hyp on the X chromosome, the following experiment was conducted. Females that were + + Hyp/+ + + were mated to a Ta Bn +/Y male (Ta = tabby; Bn = bent-tail). The (Ta Bn +/+ + Hyp)Fl females were mated to + + +/Y CBA/J males. All offspring were classified for Ta (coat texture and color), Bn (bent, shortened tail), and Hyp (shortened hind limbs).Body Weight. Offspring produced by matings of Hyp/+ females to +/Y males were weighed at birth, toe-clipped for future identification, and weighed weekly until 43 days of age.

SummaryIn MILL mice, the mostly recessive lpr mutation results in both the accumulation of CD4-, identified differences in ILNA expression and differences in the genomic organization of the Fas gene between normal and lpr mice, and confirm the recent report that a mutation in the Fas apoptosis gene is the Ipr mutation. However, our results also indicate that the Fas gene is expressed in spleen cells from normal mice, and spleen and lymph node ceils from mice with a second mutation at the Ipr locus (Ipr% Together these results suggest that altered Fas transcription results in the failure of lymphocytes to undergo programmed cell death and may lead to an altered immune cell repertoire. This mechanism may explain certain central and peripheral defects in tolerance that are present in autoimmune disease. The current study also demonstrates the profound effect of background genes on the degree of nephritis, lymphadenopathy, and anti-DNA antibody production. Of major note, our studies suggest the identification of chromosomal positions for genes that modify nephritis. Analysis of the backcross mice for markers covering most of the mouse genome suggests that over 50% of the variance in renal disease is attributable to quantitative trait loci on mouse chromosomes 7 and 12. Moreover, this study provides a model for dissecting the complex genetic interactions that result in manifestations of autoimmune disease.